A major focus of our HIV research clinic is to continue to address some of the most important aspects of HIV therapeutics, namely how to optimally use and administer multi-class combination anti-retroviral therapy in order to preserve and reconstitute immune function while at the same time minimizing long-term antiretroviral toxicities, and what are some of the predictive factors for the development of adverse consequences of progressive HIV infection both on and off antiretroviral medications. Prior Department of Health and Human Services Antiretroviral Guidelines recommended the initiation of HAART for HIV-infected individuals with CD4 cell counts of 500 cells/L or less, but also strongly recommended consideration of initiating antiretroviral treatment even in those with higher CD4 cell counts. However, these recommendations were controversial in that they were based upon the outcomes of large observational trials and expert opinion rather than on data from a randomized clinical trial. In the Clinical Research Section (CRS) of the Laboratory of Immunoregulation we contributed to the successful completion of the START study (Strategic Timing of AntiRetroviral Treatment) aimed at determining whether early introduction of ART in previously untreated patients translates into better clinical outcomes. In order to address this question more rigorously and definitively and remove the potential bias of expert opinion, the START trial is a large multi-national trial that enrolled antiretroviral-naive HIV-infected individuals with CD4 cell counts above 500 cells/L and randomly assigned them either to begin HAART immediately or to delay the start of HAART until the CD4 cell count falls below 350 cells/L. The primary goal of this 4-5 year trial was to compare the two arms in terms of the cumulative incidence of adverse consequences (both AIDS-related and non-AIDS related) ascribable either to progressive HIV infection or to the toxicities of HAART itself. The START trial enrolled 4,685 HIV-infected men and women ages 18 years or older (median age of 36 years) who had CD4+ T-cell counts above 500 cells/mm3, no symptoms of HIV infection, and had never taken antiretroviral therapy. Twenty-seven percent of the participants were women, and approximately half were gay men. In the spring of 2015 the Data Safety Monitoring Board revealed that the primary endpoint of START had been achieved. Data analysis revealed that the risk of developing serious AIDS, serious non-AIDS, or death was reduced by 57 percent among those in the early treatment group compared to those in the deferred group. This reduction was seen regardless of age, sex, baseline CD4+ cell counts, geographic region or country income level. The most common events observed in the study were non-AIDS events that typically affect older individuals. The two most common individual serious non-AIDS events in the immediate and deferred groups were cardiovascular disease (12 and 14 participants with events, respectively) and non-AIDS-defining cancer (9 and 18 participants with events, respectively). Most of the tuberculosis occurred among participants at study sites in Africa (16 of 26 events), where both TB and HIV/AIDS are endemic. The START trial is now in extended follow-up through at least the year 2021 during which a number of important subsidies are underway and additional insights are likely to be gleaned.